The present invention refers to new alkylating antitumor and antiviral agents related to the known antibiotic distamycin A: 
which belongs to the family of the pyrroleamidine antibiotics and is reported to interact reversibly and selectively with DNA-AT sequences interfering with both replication and transcription [Nature, 203, 1064 (1964); FEBS Letters, 7 (1970) 90; Prog. Nucleic Acids Res. Mol. Biol., 15, 285 (1975)].
DE-A-1795539 describes the preparation of distamycin derivatives in which the formyl group of distamycin is replaced by hydrogen or by the acid residue of an organic C1-C4 aliphatic acid or of cyclopentylpropionic acid. EP-B-246,868 describes distamycin analogues in which the distamycin formyl group is substituted by aromatic, alicyclic or heterocyclic moieties bearing alkylating. groups.
International patent application WO 90/11277 discloses a broad class of acryloyl substituted distamycin derivatives wherein the acryloyl moiety is linked to the pyrrole ring through a single bond or an aromatic or heterocyclic dicarboxamide group.
It has now been found that a new class of distamycin derivatives as defined hereinunder, wherein the distamycin formyl group is substituted by an acryloyl moiety while the amidine group is substituted by different nitrogen-containing end-groups, shows valuable biological properties.
Accordingly, the present invention relates to new distamycin derivatives of formula (I) as defined hereinunder, to a process for preparing them, to pharmaceutical compositions containing them and to their use in therapy, particularly as antitumor and antiviral agents.
Therefore, object of the present invention are acryloyl substituted distamycin derivatives of formula: 
wherein:
n is 2, 3 or 4;
R1 and R2 are selected, each independently, from: hydrogen, halogen, and C4-C4 alkyl;
R3 is hydrogen or halogen;
B is selected from: 
xe2x80x83wherein R4, R5, R6, R7, and R8 are, each independently, hydrogen or C1-C4 alkyl, with the proviso that at least one of R4, R5 and R6 is C1-C4 alkyl;
or pharmaceutically acceptable salts thereof.
The present invention includes within its scope also all the possible isomers covered by formula (I) both separately and as a mixture, as well as the metabolites and the pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I).
The alkyl groups may have branched or straight chains. A C1-C4 alkyl group is preferably methyl or ethyl. A halogen atom is preferably chlorine, bromine or fluorine. Preferably, R4, R5, R6, R7, and R8 are, each independently, hydrogen, methyl, or ethyl, with the proviso that at least one of R4, R5 and R6 is methyl or ethyl.
Pharmaceutically acceptable salts of the compounds of formula (I) are their salts with pharmaceutically acceptable, either inorganic or organic, acids. Examples of inorganic acids are hydrochloric, hydrobromic, sulfuric and nitric acid; examples of organic acids are acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid.
A preferred class of compounds according to the present invention is that of formula (I) wherein:
n is 3 or 4;
R1 and R2 are hydrogen;
R3 is chlorine or bromine;
B is selected from: 
xe2x80x83wherein R4, R5, R6, R7, and R8 are, each independently, hydrogen or methyl, with the proviso that at least one of R4, R5 and R6 is methyl;
or the pharmaceutically acceptable salts thereof.
Examples of specific compounds according to the present invention, especially in the form of salts, preferably with hydrochloric acid, are the following:
(1) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromo-acrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propioncyanamidine;
(2) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propioncyanamidine;
(3) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propioncyanamidine;
(4) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromo-acrylamido)pyrrole2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamidine;
(5) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamidine;
(6) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamidine;
(7) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromo-acrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,Nxe2x80x2-dimethylamidine;
(8) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,Nxe2x80x2-dimethylamidine;
(9) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,Nxe2x80x2-dimethylamidine;
(10) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromo-acrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime;
(11) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime;
(12) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime;
(13) 2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromo-acrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)ethylguanidine;
(14) 2-(1-methyl-4-(1-methyl-4-(-methyl-4-(1-methyl-4-(xcex1-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)ethylguanidine;
(15) 2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)ethylguanidine;
(16) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromo-acrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionitrile;
(17) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionitrile;
(18) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionitrile;
(19) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromo-acrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) pyrrole-2-carboxamido)propionamide;
(20) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamide;
(21) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamide;
(22) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamide;
(23) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromoacrylamido)pyrrole-2carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N-dimethylamidine;
(24) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N-dimethylamidine;
(25) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N-dimethylamidine;
(26) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methyl-amidine;
(27) 3-(1-methyl-4-(1-methyl-4-(xcex1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,Nxe2x80x2-dimethyl-amidine;
(28) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime;
(29) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propioncyanamidine; and
(30) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(xcex1-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamide.
The compounds of formula (I) and the salts thereof, object of the present invention, can be prepared according to one of the following processes, which comprise:
(a) reacting a compound of formula: 
xe2x80x83wherein:
n is 2, 3 or 4;
m is 0 or 1;
B is selected from: 
xe2x80x83wherein R4, R5, R6, R7, and R8 are, each independently, hydrogen or C1-C4 alkyl, with the proviso that at least one of R4, R5 and R6 is C1-C4 alkyl;
with a compound of formula: 
xe2x80x83wherein: R1 and R2 are selected, each independently, from: hydrogen, halogen, and C1-C4 alkyl; R3 is hydrogen or halogen; X is hydroxy or a leaving group; and m has the above reported meanings;
or:
(b) when B is equal to xe2x80x94Cxe2x89xa1N, reacting a compound of formula: 
xe2x80x83wherein n, R1, R2, and R3 are as defined above;
with succinic anhydride, and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.
In the compounds of formula (III), X is hydroxy or a leaving group selected, for instance, from chloro, 2,4,5-trichlorophenoxy, 2,4-dinitro-phenoxy, succinimido-N-oxy, imidazolyl group, and the like.
The reaction of process (a) between a compound of formula (II) and a compound of formula (III) can be carried out according to known methods, for instance those described in EP-B-246,868.
The reaction between a compound of formula (II) and a compound of formula (III) wherein X is hydroxy, is preferably carried out with a molar ratio (II):(III) of from 1:1 to 1:2, in an organic solvent, such as, e.g., dimethylsulfoxide, hexamethylphosphotriamide, dimethyl-acetamide, dimethyl-formamide, ethanol, benzene, or pyridine, in the presence of an organic or inorganic base such as, e.g., triethylamine, diisopropyl ethylamine, or sodium or potassium carbonate or bicarbonate, and of a condensing agent such as, e.g., N-ethyl-Nxe2x80x2-(3-dimethylamino-propyl)-carbodiimide, N,Nxe2x80x2-dicyclo-hexylcarbodiimide, and/or 1-hydroxy-benzotriazole hydrate. The reaction temperature may vary from about xe2x88x9210xc2x0 C. to about 100xc2x0 C., and the reaction time from about 1 to about 24 hours.
The reaction between a compound of formula (II) and a compound of formula (III), wherein X is a leaving group as defined above, may be carried out with a molar ratio (II): (III) of from about 1:1 to about 1:2, in an organic solvent, such as, e.g., dimethylformamide, dioxane, pyridine, benzene, tetrahydrofurane, or mixtures thereof with water, optionally in the presence of an organic base, e.g. N,Nxe2x80x2-diisopropylethylamine, triethylamine, or an inorganic base, e.g. sodium or potassium bicarbonate, at a temperature of from about 0xc2x0 C. to about 100xc2x0 C., and for a time varying from about 2 hours to about 48 hours. The optional conversion of a compound of formula (I) into a pharmaceutically acceptable salt thereof may be carried out by conventional known method.
The compounds of formula (II) are known compounds, or can be obtained by known methods (see e.g. Tetrahedron Letters 31, 1299 (1990), Anti cancer Drug Design 9, 511 (1994)), such as:
(i) by hydrolitic deformylation, in a basic or acid medium, of compounds of formula: 
or
(ii) by nitro-group reduction, according to known methods, of compounds of formula: 
xe2x80x83wherein in the compounds of formula (V) and (VI):
n is 2, 3 or 4; m is 0 or 1;
is selected from: 
xe2x80x83wherein R4, R5, R6, R7, and R8 are, each independently, hydrogen or C1-C4 alkyl, with the proviso that at least one of R4, R5 and R6 is C1-C4 alkyl.
The compounds of formula (V), except when B is equal to 
can in turn be prepared starting from distamycin analogues of formula: 
by using:
(i) H2Nxe2x80x94CN, so obtaining a compound of formula (I) having B equal to: 
(ii) H2Nxe2x80x94OH, so obtaining a compound of formula (I) having 
(iii) H2Nxe2x80x94NH2, so obtaining a compound of formula (I) having B equal to: 
(iv) HNR4R5, so obtaining a compound of formula (I) having B equal to: 
xe2x80x83and then optionally with H2NR6, so obtaining a compound of formula (I) having B equal to: 
xe2x80x83wherein R4, R5, and R6 are, each independently, hydrogen or C1-C4 alkyl, with the proviso that at least one of R4, R5, and R6 is C1-C4 alkyl;
(v) succinic anhydride, so obtaining a compound of formula (I) having B equal to xe2x80x94Cxe2x89xa1N;
(vi) water in an alkaline medium, so obtaining a compound of formula (I) having B equal to xe2x80x94COxe2x80x94NR7R8 wherein R7 and R8 are both hydrogen; (vii) HNR7R8, so obtaining a compound of formula (I) having B equal to: 
xe2x80x83and then with water in an alkaline medium, so obtaining a compound of formula (I) having B equal to xe2x80x94COxe2x80x94NR7R8, wherein R7 and R8 are, each independently, hydrogen or C1-C4 alkyl, with the proviso that at least one of R7 and R8 is C1-C4 alkyl.
The reaction between a compound of formula (VII) and one of the reactants as described at points (i), (ii), (iii), (iv), or (vii) can be carried out according to known methods, for instance those reported in: U.S. Pat. No. 4,766,142, Chem. Revs. 1961, 155; J. Med. Chem. 1984, 27, 849-857; Chem. Revs. 1970, 151; and xe2x80x9cThe Chemistry of Amidines and Imidatesxe2x80x9d, edited by S. Patai, John Wiley and Sons, N.Y. (1975).
The reaction of a compound of formula (VII) with succinic anhydride (see point (v) above) is preferably carried out with a molar ratio (VII):succinic anhydride of from 1:1 to 1:3 in an organic solvent such as, e.g., dimethylsulfoxide, dimethylformamide, in the presence of an organic or inorganic base such as, e.g., triethylamine, diisopropylethylamine, sodium or potassium carbonate, and the like. The reaction temperature may vary from about 25xc2x0 C. to about 100xc2x0 C., and the reaction time from about 1 hour to about 12 hours.
The reaction with water in an alkaline medium (see points (vi) and (vii) above) may be carried out according to known methods usually employed for an alkaline hydrolysis, e.g. by treating the substrate with an excess of sodium or potassium hydroxide dissolved in water or in a mixture of water with an organic solvent, e.g. dioxane, tetrahydrofurane, or acetonitrile, at a temperature of from about 50xc2x0 to about 100xc2x0 C., for a time varying from about 2 hours to about 48 hours.
The compounds of formula (III) are known compounds or may be prepared starting from known compounds through reactions well known in organic chemistry: see, for instance, J.C.S. 1947-1032 and JACS 62, 3495 (1940).
The compounds of formula (VI) can be obtained:
(i) except when B is equal to 
xe2x80x83from a compound of formula: 
xe2x80x83wherein n, m and X are as defined above, by reaction with a compound of formula: 
wherein Bxe2x80x2 is selected from: 
(ii) except when B is equal to 
Pinner reaction of a compound of formula: 
xe2x80x83with a suitable amine compound as defined at point (i), (ii), (iii) or (iv) above.
The compounds of formulas (VII), (VIII), (IX) and (X) are known compounds, or may be obtained by known methods (see e.g. Tetrahedron, 34, 2389-2391, 1978; J. Org. Chem., 46, 3492-3497, 1981).
The reaction of process (b) is preferably carried out with a molar ratio (IV):succinic anhydride of from 1:1 to 1:3 in an organic solvent such as, e.g., dimethylsulfoxide or dimethylformamide, in the presence of an organic or inorganic base such as, e.g., triethylamine, diisopropylethylamine, sodium or potassium carbonate, and the like. The reaction temperature may vary from about 25xc2x0 C. to about 100xc2x0 C., and the reaction time from about 1 hour to about 12 hours.
The compounds (IV) can be obtained with known methods, for example, those described in WO 90/11277.
Salification of a compound of formula (I), as well as preparation of a free compound starting from a salt, may be carried out by known standard methods.
Well known procedures such as, e.g., fractional crystallization or chromatography, may also be followed for separating a mixture of isomers of formula (I) into the single isomers.
The compounds of formula (I) may be purified by conventional techniques such as, e.g., silica gel or alumina column chromatography, and/or by recrystallization from an organic solvent such as, e.g., a lower aliphatic alcohol, e.g. methyl, ethyl or isopropyl alcohol, or dimethylformamide.
The compounds of formula (I) according to the present invention are useful as antineoplastic and antiviral agents. Particularly, they show cytostatic properties towards tumor cells, so that they can be useful to inhibit growth of various tumors in mammals, including humans, such as, for instance, carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors. Other neoplasias in which the compounds of the present invention can find application are, for instance, sarcomas, e.g. soft tissue and bone sarcomas, and the hematological malignancies such as, e.g. leukemias.
The in vitro antitumor activity was evaluated by cytotoxicity studies carried out on murine L1210 leukemia cells. Cells were derived from in vivo tumors and established in cell culture. Cells were used until the tenth passage. Cytotoxicity was determined by counting surviving cells after 48 hours treatment.
The percentage of cell growth in the treated cultures was compared with that of controls. IC50 values (concentration inhibiting 50% of the cellular growth in respect to controls) were calculated on dose-response.
The compounds of the invention were tested also in vivo on L1210 murine leukemia and on murine reticulosarcoma M 5076, showing a very good antitumoral activity, with the following procedure.
L1210 murine leukemia was maintained in vivo by i.v. serial transplantation. For experiments, 105 cells were injected i.p. in CD2F1 female mice, obtained from Charles River Italy Animals were 8 to 10 weeks old at the beginning of the experiments. Compounds were administered i.v. at day +1 after tumor cells injections.
M5076 reticulosarcoma was maintained in vivo by i.m. serial transplantation. For experiments, 5+105 cells were injected i.m. in C57B16 female mice, obtained from Charles River Italy. Animals were 8 to 10 weeks old at the beginning of the experiments. Compounds were administered i.v. at day 3, 7 and 11 after tumor injection.
Survival time of mice and tumor growth were calculated and activity was expressed in term of T/C % and T.I. %.                               T          /          C                =                                            median              ⁢                              xe2x80x83                            ⁢              survival              ⁢                              xe2x80x83                            ⁢              time              ⁢                              xe2x80x83                            ⁢              treated              ⁢                              xe2x80x83                            ⁢              group                                      median              ⁢                              xe2x80x83                            ⁢              survival              ⁢                              xe2x80x83                            ⁢              time              ⁢                              xe2x80x83                            ⁢              untreated              ⁢                              xe2x80x83                            ⁢              group                                xc3x97          100                                                  T          .          I          .                =                  %          ⁢                                    xe2x80x83                        ⁢                          xe2x80x83                                ⁢          inhibition          ⁢                      xe2x80x83                    ⁢          of          ⁢                      xe2x80x83                    ⁢          tumor          ⁢                      xe2x80x83                    ⁢          growth          ⁢                      xe2x80x83                    ⁢          respect          ⁢                      xe2x80x83                    ⁢          to          ⁢                      xe2x80x83                    ⁢          control                    
Tox: number of mice which died for toxicity. Tox determination was made when mice died before the control and/or tested significant body weight loss and/or spleen and/or liver size reduction were observed.
The compounds of the invention show also a remarkable effectiveness in interfering with the reproductive activity of pathogenic viruses and protect tissue cells from viral infections. For example, they show activity against DNA viruses such as, for instance, herpes, e.g. herpes simplex and herpes zoster viruses, virus vaccinia, RNA viruses such as, e.g., Rhinovirus and Adenovirus, and against retroviruses such as, for instance, sarcoma viruses, e.g., urine sarcoma virus, and leukemia viruses, e.g. Friend leukemia virus.
For example, effectiveness against herpes, coxsackie and respiratory syncytial viruses was tested in a fluid medium as follows. Serial two-fold dilutions of the compounds from 200 to 1.5 mcg/ml were distributed in duplicate 0.1 ml/well in 96 well microplates for tissue culture. Cell suspensions (2xc3x97105 cells/ml) infected with about 5xc3x9710xe2x88x923 TClD50 of virus/cell were immediately added 0.1 ml/well.
After 3-5 day incubation at 37xc2x0 C. in CO2 5%, the cell cultures were evaluated by microscope observation and Minimum Inhibiting Concentration (MIC) was determined, MIC being the minimum concentration which determines a reduction of cytopathic effect in comparison with the infected controls.
The compounds of the invention can be administered to mammals, including humans, through the usual routes, for example, parenterally, e.g. by intravenous injection or infusion, intramuscularly, subcutaneously, topically or orally. The dosage depends on the age, weight and conditions of the patient and on the administration route. For example, a suitable dosage for administration to adult humans may range from about 0.1 to about 150-200 mg pro dose 1-4 times a day.
Further object of the present invention are pharmaceutical compositions, which comprise a compound of formula (I) as an active principle, in association with one or more pharmaceutically acceptable carrier and/or diluent.
The pharmaceutical compositions of the present invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. For instance, solutions for intravenous injection or infusion may contain as a carrier, for example, sterile water or preferably, they may be in the form of sterile aqueous isotonic saline solutions.
Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
In the forms for topical application, e.g. creams, lotions or pastes for use in dermatological treatment, the active ingredient may be mixed with conventional oleaginous or emulsifying excipients.
The solid oral forms, e.g. tablets and capsules, may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch and potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinyl-pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, polysorbates, laurylsulfates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulation. Said pharmaceutical preparation may be manufactered by known techniques, for example by means of mixing, granulating, tabletting, sugar-coating or film-coating processes.
A further object of the present invention are the compounds of formula (I) for use in a method for treating the human or animal body by therapy.
Furthermore, the present invention provides a method for treating tumors and viral infections in a patient in need of it, which comprises administering to said patient a composition of the invention.
A further object of the present invention is a combined method for treating cancer or for ameliorating the conditions of mammals, including humans, suffering from cancer, said method comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an additional antitumor agent, close enough in time and in amounts sufficient to produce a therapeutically useful effect.
The present invention also provides combined preparations for simultaneous, separate or sequential use in anti-cancer therapy, comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an additional antitumour agent.
The term xe2x80x9cantitumor agentxe2x80x9d is meant to comprise both a single antitumor drug and xe2x80x9ccocktailsxe2x80x9d i.e. a mixture of such drugs, according to the clinical practice. Examples of antitumor agents that can be formulated with a compound of formula (I), or alternatively, can be administered in a combined method of treatment, include doxorubicin, daunomycin, epirubicin, idarubicin, etoposide, fluoro-uracil, melphalan, cyclo-phosphamide, 4-demethoxy daunorubicin, bleomycin, vinblastin, and mitomycin, or mixtures thereof.